Hydantoin compounds



Patented Aug. 24, 1954 UNITED STATES PATENT OFFICE HYDANTOIN COMPOUNDS Walther Persch, Frankfurt (Main) Hochst, and

- Adolf Schmidt, Frankfurt (Main) Fechenheim, Germany, assignors to Cassella Farbwerke Mainkur Aktiengesellschaft, Frankfurt Main) company Fechenheim,

Germany, a German No Drawing. Application February 19, 1951,

Serial No. 211,794

Claims priority, application Germany March 6, 1950 3 Claims.

- 1 This invention relates to new hydantoin compounds.

It is known to use hydantoins, e. g., diphenylhydantoin, against genuine epilepsis and against the pathological symptoms of brain trauma owing to their action of alleviating or removing the seizures. It is further known that epileptics resistant to barbituric acid can be treated with success by hydantoin's. I

It has now been found that the hydantoins of the general formula:

O O-R I N RIII 4 3 v 67% 2| (wherein R means a radical of the group consisting of hydrogen, aryl, alkyl which latter may contain'a' basic group; R means a radical of the group consisting of hydrogen, alkyl, aryl; R" and R mean each a radical of the group consisting of hydrogen, aralkyl and alkyl), which hydantoins are new compounds, show, besides the antiepileptic action customary for hydantoins, a peculiar and predominant hypnotic action.

These new compounds may be prepared as follows: compounds of the formula:

the hydantoins thus prepared further substituents may be introduced, e. g. alkyl groups, especially when R and R 01 the primarily prepared (c1. zen-309.5)

2 hydantoins are hydrogen, or bromine atoms when the radicals R, R, R" or R' mean an unsaturated group, or alkylamino groups when the radicals R, R, R" or R' contain substituents convertible into such groups.

The following examples illustrate the invention, but they are not intended to limit it thereto.

EXAMPLE 1 5 (o-hydromyphe'nyl) -5-methyZ-hydantcin 204 grs. of o-hydroxyacetophenone, 120 grs. of potassium cyanide, 240 grs. of ammonium bicarbonate, 500 ccm. of ethanol and 600 com. of water are stirred for 12 hours under a COz-pressure of 15-17 atm. When worked up, the crystals obtained represent-after a recrystallization from ethanol-pure 5 (o hydroxyphenyl) 5- methyl-hydantoin of a melting-point of 229- 230.5 C.

1 EXAMPLE 2 5 (p -allylom'ypltenyl) -5-methyZ-hydantoz'n 88 grs.; of p-allyloxy-acetophenone (obtained from p-hydroxy-acetophenone and allylbromide) 40 grs. of potassium cyanide, 75 grs. of ammoniumbicarbonate, 200 com. of ethanol and 250 com. of water are stirred for 15 hours in an autoclave at 16-18 atm. COz-pressure at 70-75 C. The crystals obtained show--after a recrystallization from methanol--a melting-point of 171 C.

} EXAMPLE 3 5-0(p-diethylamino-ethoxy) -phenyl-5- propyZ-hydantozn 61 grs. .of o(,6-diethylaminoethoxy)-butyrophenone (at room-temperature an oil of a boiling point of 175-176? C. at 2 mm., prepared from ohydroXy-butyrophenone and diethylamino-chlorethane), 30 grs. of potassium cyanide, grsl of ammonium carbonate, 250 com. of water and 200 com. of ethanol are stirred in an autoclave for 10 hoursat -80 C. and 14-17 atm. The crystals obtained recrystallize from methanol as pure White crystals of a melting point of 156 C.

EXAMPLE 4 5- (o-hydrotc yphenyl) -1-N(n) butyl-hydantoin 121 grs. of freshly distilled salicylaldehyde are converted by grs. of n-butylamine into the imine. This is dropped at a temperature of about 5 C. to a mixture of 400 grs. of 75% acetic acid and 38 grs. of potassium cyanide, which mixture is stirred in a cooling bath at about C. Another 38 grs. of potassium cyanide are then added gradually. When the temperature is again at 0 (3., 87 grs. of potassium cyanate are added within half an hour, the temperature being kept below C. After stirring at room temperature for 1 hour, the temperature is slowly raised to 19 70 C. and stirring is continued for minutes at this temperature. At .C. 300 com. of concentrated hydrochloric acid are added by dropping, initial cooling being applied. Stirring is then continued for 1 more hour at.9,0 C. Thereupon about 3 litres of ice-waterare added and the Whole is kept in ice during one night. The separated crystals are recrystallized twice from methanol, some charcoal being added. Thus almost white crystals are obtained of a meltingpoint of 191 C.

EXAMPLE 5 5-10 (B- -dibrom0pr0p0ryphenyl) -5-methylhydcmtoz'n At room temperature 8 grs. of bromine in 163 com. of dry chloroform are dropped into 12.3 grs. of 5-p-allyloxy-pheny15-methyl-hydantoin (prepared as outlined in Example 2)., dissolved in about 1700 ccm. of dry chloroform. After stirring during several hours, the chloroform is removed under vacuum. The residue is recrystallized with some charcoal ifrom.methanol, deliver- 4 ing white crystals with a melting-point of 180- 183 C.

EXAMPLE 6 5 -p-phewo:ryphenyl5-methyZ-hydamtoin 88 grs. of pephenoxyacetophenone (boilingpoint: 174178 C. at 1 mm), 35 grs. of potassium cyanide, grs. of ammoniumbicarbonate are stirred with 250 com. of water and 250 ccm. of alcohol in an autoclave under 20 atm. CO2- pressure at -75 C. for 15 hours. The raw product is sucked on and after recrystallizing it twice from alcohol, pure 5-p-phenoxy-phenyl- 5-methy1-hydantoin is obtained with a meltingpoint of 182 C.

EXAMPLE 7 3-methyZ-5 -methyl- 5 -p-allyloxyphenylhydantoin N0. R R R' Fp., degrees 1 OH H H 244-246.

2... C H H H 268-261.

. 3... C H H 245- 4... 0H 0 H; H H 213-214.

5.. 0H 08mm) H H 218. u.

6.. C H H 151.

7.. C H H H 1 9.

CIHOQ a 7(n) 7 8... 0 Q1115 OH; H H 181-182. 5.

9......... 003 03H; H H 184-166.

10.. 0 Cal-I5 C:H7(1l) H H 158-159.

7 r We claim: 1. Hydantoin compounds corresponding to th general formula 7 o-NH 1 CH: BIT-0:0

which compound represents when recrystallized from an alcohol white *orfeebly yellow crystals melting at 299-2305 0. and is distinguished by 8. an antieplleptic and simultaneously a hypnotic action.

3. The hydantoin compound of the formula:

which compound represents when recrystallized from an alcohol white or feebly yellow crystals melting at 273 C. and is distinguished by an antiepileptic and simultaneously a hypnotic action.

References Cited in the file of this patent Chemical Abstracts, vol. 42, 11.3372 citing Gorvin, Nature, 161, .page 208 (1948).

Chemical Abstracts, vol. 41, p. 6885 citing Mel-- ton et al.-Jr. Am. Chem. Soc.--'69-.p.2018-18 (194.7).

Henze, Jr. Amer. Chem. Soc., vol. 64, p. 522-3 (1942.)

Chemical Abstracts, vol. 30, p. 4474 citing Berichtepp. 566--5"72 (1936). 

1. HYDANTOIN COMPOUNDS CORRESPONDING TO THE GENERAL FORMULA 